It has been recognized for over a century that the anterior chamber (AC) of the eye is endowed with remarkable properties that permit the long-term survival of histoincompatible tissue and tumor grafts. Ocular immune privilege is the product of multiple, overlapping physiological, anatomical, and immunoregulatory properties of the eye. One of thee mechanisms is the dynamic down-regulation of antigen-specific Th1 and Th2 immune responses and alterations in isotype switching of antibody production. This phenomenon has been termed anterior chamber-associated immune deviation (ACAID) and has been a major focus of the Pi's laboratory for the past 25 years. In this application, we propose to characterize another curious form of immune deviation that is revealed when interferon-y (IFN-Y) is not available during the initial immune response to antigens introduced into the AC. This immune deviation is a sharp departure from ACAID. The prototype model for this form of ocular immune deviation is revealed when adenovirus-induced tumor cells (Ad5E1) are introduced into the AC of syngeneic C57BL/6 mice. Intraocular tumors undergo a form of immune rejection that is: a) DTH- independent; b) cytotoxic T lymphocyte (CTL)-independent; c) CD4+ T cell-dependent; and d) interferon-Y (IFN-v)-dependent. By contrast, tumor cells transplanted subcutaneously (SC) undergo immune rejection and prevent the growth of intraocular Ad5E1 tumors in IFN-y KO mice, indicating that the protective immune response elicited outside of the eye is IFN-y-independent. The SC-induced immunity that prevents intraocular tumor growth is: a) DTH-independent; b) IFN-y-independent; c) P2microglobulin (p2M)-independent; and d) CTL-independent. This project will characterize and analyze this unique form of ocular immune deviation and intraocular tumor immunity. We propose that there are two fundamental pathwaysfor the rejection of immunogenic intraocular tumors, such as Ad5E1. The first pathway is IFN-y-dependent and is induced by intraocular tumors. The second pathway is IFN-y-independent and CTL-independent, and is induced by extraocular tumors and mediates rejection of intraocular tumors. This project will address three specific aims pursuant to these forms of intraocular tumor rejection: 1) characterize the IFN-y-dependent mechanisms of tumor rejection; 2) characterize the IFN-y-independent mechanisms of tumor rejection; and 3) determine the role of IFN-y in tne induction ofACAID.